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101.
The hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in 6-
thioguanine (TG) resistant T-lymphocytes is a useful target for the study
of somatic in vivo mutagenesis, since it provides information about a broad
spectrum of mutation. Mutations in the hprt coding region were studied in
124 TG-resistant T-cell clones from 38 healthy, non- smoking male donors
from a previously studied population of bus maintenance workers,
fine-mechanics and laboratory personnel. Their mean age was 43 years (range
23-64) and their hprt mutant frequency was 9.3 +/- 5.2 x 10(-6) (mean +/-
SD, range 1.4-22.6 x 10(-6)). Sequence analysis of hprt cDNA identified 115
unique mutations; 76% were simple base substitutions, 10% were +/-1 bp
frameshifts, and 10% were small deletions within exons (3-52 bp). In
addition, two tandem base substitutions and one complex mutation were
observed. Simple base substitutions were observed at 55 (20%) of 281 sites
known to be mutable in the hprt coding sequence. The distribution of these
mutations was significantly different than would be expected based upon a
Poisson distribution (P < 0.0001), suggesting the existence of
'hotspots'. All of the 87 simple base substitutions occurred at known
mutable sites, but eight were substitutions of a kind that have not
previously been reported at these sites. The most frequently mutated sites
were cDNA positions 197 and 146, with six and five independent mutations
respectively. Four mutations were observed at position 131, and three each
at positions 143, 208, 508 and 617. Transitions (52%) were slightly more
frequent than tranversions (48%), and mutations at GC base pairs (56%) more
common than mutations at AT base pairs (44%). GC > AT was the most
common type of base pair substitution (37%). The majority of the mutations
at GC base pairs (78%) occurred at sites with G in the non-transcribed
strand. All but one of eight mutations at CpG- sites were of the kind
expected from deamination of methylated cytosine. Deletion of a single base
pair (-1 frameshift) was three times more frequent than insertion of a
single bp (+1 frameshift). Almost half (6/13) of the small (3-52 bp)
deletions within the coding sequence clustered in the 5' end of exon 2.
Short repeats and other sequence motifs that have been associated with
replication error were found in the flanking regions of most of the
frameshifts and small deletions. However, several differences in the local
sequence context between +/-1 frameshift and deletion mutations were also
noticed. The present results identify positions 197, 146 and possibly 131
as hotspots for base substitution mutations, and confirm previously
reported hotspots at positions 197, 508 and 617. In addition, the earlier
notion of a deletion hotspot in the 5'end of exon 2 was confirmed. The
observations of these mutational cluster regions in different human
populations suggest that they are due to endogeneous mechanisms of
mutagenesis, or to ubiquitous environmental influences. The emerging
background spectrum of somatic in vivo mutation in the human hprt gene
provides a useful basis for comparisons with radiation or chemically
induced mutational spectra, as well as with gene mutations in human tumors.
相似文献
102.
103.
Phenobarbital and clofibrate, two non-genotoxic carcinogens, have been
investigated regarding the relationship between reactive oxygen species,
antioxidant enzyme expression and apoptosis in primary cultures of rat
hepatocytes. Low toxicity concentrations, 200 and 100 microg/ml for
phenobarbital and clofibrate respectively, were used to examine their
effect on spontaneous or transforming growth factor beta1
(TGFbeta1)-induced apoptosis and on the expression of antioxidant defence
enzymes (superoxide dismutases and catalase). The increased incidence of
apoptotic nuclei was visualized in TGFbeta1-treated cultures with the
fluorescent dye Hoechst 33258 and was quantified under all experimental
conditions by measurement of the hypodiploid peak in DNA histograms
obtained by flow cytometry. Both substances, when added separately to
hepatocyte cultures and incubated for 24 and 48 h, significantly diminished
spontaneous apoptosis and exhibited a slight suppression of
TGFbeta1-induced apoptosis. Endogenous peroxide production by hepatocytes
increased with TGFbeta1, phenobarbital or clofibrate and the increase was
greater with phenobarbital and in the presence of TGFbeta1 with both drugs.
Gene expression of catalase and Mn- and Cu,Zn superoxide dismutases (SOD)
was evaluated by northern blot analysis of hepatocytes incubated in the
presence of phenobarbital or clofibrate with or without TGFbeta1 and the
following differences were detected: phenobarbital induced a significant
decrease in both dismutases (to 56%, P < 0.05, and 55%, P < 0.05, for
Mn- and Cu,Zn-SOD respectively) and a 2-fold increase (P < 0.01) in
catalase; clofibrate induced a slight decrease in both SODs and a 4-fold
increase (P < 0.05) in catalase; TGFbeta1 significantly decreased to 37%
(P < 0.05) expression of catalase while not significantly affecting
expression of both SODs. We conclude that inhibition of spontaneous
apoptosis induced by either phenobarbital or clofibrate is accompanied by
increases in the endogenous levels of peroxides and by significant
induction of catalase gene expression. Furthermore, the lack of effect of
both compounds on TGFbeta1-induced apoptosis could be a consequence of the
inability of these two compounds to counteract the depressing effect of
TGFbeta1 on expression of catalase.
相似文献
104.
Assessing the Efficiency of HIV Prevention around the World: Methods of the PANCEA Project
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Elliot Marseille Lalit Dandona Joseph Saba Coline McConnel Brandi Rollins Paul Gaist Mattias Lundberg Mead Over Stefano Bertozzi James G. Kahn 《Health services research》2004,39(6P2):1993-2012
Objective. To develop data collection methods suitable to obtain data to assess the costs, cost-efficiency, and cost-effectiveness of eight types of HIV prevention programs in five countries.
Data Sources/Study Setting. Primary data collection from prevention programs for 2002–2003 and prior years, in Uganda, South Africa, India, Mexico, and Russia.
Study Design. This study consisted of a retrospective review of HIV prevention programs covering one to several years of data. Key variables include services delivered (outputs), quality indicators, and costs.
Data Collection/Extraction Methods. Data were collected by trained in-country teams during week-long site visits, by reviewing service and financial records and interviewing program managers and clients.
Principal Findings. Preliminary data suggest that the unit cost of HIV prevention programs may be both higher and more variable than previous studies suggest.
Conclusions. A mix of standard data collection methods can be successfully implemented across different HIV prevention program types and countries. These methods can provide comprehensive services and cost data, which may carry valuable information for the allocation of HIV prevention resources. 相似文献
Data Sources/Study Setting. Primary data collection from prevention programs for 2002–2003 and prior years, in Uganda, South Africa, India, Mexico, and Russia.
Study Design. This study consisted of a retrospective review of HIV prevention programs covering one to several years of data. Key variables include services delivered (outputs), quality indicators, and costs.
Data Collection/Extraction Methods. Data were collected by trained in-country teams during week-long site visits, by reviewing service and financial records and interviewing program managers and clients.
Principal Findings. Preliminary data suggest that the unit cost of HIV prevention programs may be both higher and more variable than previous studies suggest.
Conclusions. A mix of standard data collection methods can be successfully implemented across different HIV prevention program types and countries. These methods can provide comprehensive services and cost data, which may carry valuable information for the allocation of HIV prevention resources. 相似文献
105.
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107.
AM Halefoglu 《Journal of Medical Imaging and Radiation Oncology》2005,49(3):242-245
A pulmonary arteriovenous fistula is an abnormal connection between pulmonary arteries and veins. Patients with Rendu–Osler–Weber syndrome may present with this vascular malformation, which is a typical finding of the disease. Approximately 5–15% of Rendu–Osler–Weber syndrome patients have pulmonary arteriovenous malformations (AVM) and there is usually a family history of AVM in these patients. The malformations are usually located in the lower lobes. In this paper, I describe a 49‐year‐old male patient with dyspnoea, cough, haemoptysis and epistaxis. Physical examination showed nasal telangiectasias, cyanosis of the lips and nails, and a systolic bruit over the left lung. Chest X‐ray revealed a 5‐cm mass in the left lower lobe and after magnetic resonance examination, together with 3‐D magnetic resonance angiography, it was demonstrated to be a pulmonary arteriovenous fistula. The history of a niece with a similiar history of suspected pulmonary arteriovenous fistula led me to consider the possibility of Rendu–Osler–Weber syndrome presenting with a pulmonary arteriovenous fistula. 相似文献
108.
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110.